Bone metastases with “false negative” findings on 18F-FDG PET/CT in patients with angiosarcoma: A case series with literature review

Rationale: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is considered a reliable and indispensable imaging method when evaluating distant metastases and clinical staging of angiosarcomas. Here, we report 2 cases of angiosarcoma with bone metastases with “false negative” findings on 18F-FDG PET/CT. Patient concerns: Case 1, a 39-year-old woman, who had undergone mastectomy for primary angiosarcoma 2 years prior, presented with a 5-month history of right coxalgia. Case 2 was a 37-year-old woman, who had undergone mastectomy for primary angiosarcoma 4 months prior. During postoperative follow-up, multiple bone lesions were detected on magnetic resonance imaging (MRI). Diagnoses: Based on the histopathological findings, both cases were diagnosed with bone metastases of angiosarcoma. Although MRI showed multiple bone metastatic lesions, 18F-FDG PET/CT showed no uptake or osteolytic destruction in both cases. Interventions: Weekly paclitaxel was initiated as a salvage chemotherapy in both cases. Outcomes: No uptake or osteolytic lesions were observed on 18F-FDG PET/CT, despite multiple bone metastases detected on MRI. Lessons: False-negative findings on 18F-FDG PET/CT should be considered when evaluating bone metastases of angiosarcoma. Even with negative findings on 18F-FDG PET/CT, open biopsy should be performed if MRI indicates bone metastases.


Introduction
Angiosarcoma is a malignant soft tissue tumor of vascular origin that accounts for 1% to 2% of all the soft tissue sarcomas. [1,2] Angiosarcomas have poor prognosis with rapid progression and 5-year survival rate of approximately 10% to 50%. [3,4] Surgery, tumor localization, tumor size, performance status, and histopathology have been reported as prognostic factors for angiosarcoma, among which the presence of distant metastasis at the initial diagnosis is reported to be an independent prognostic factor for the overall survival rate. [5,6] Reportedly, angiosarcomas can easily metastasize to other parts of the body through the blood or lymphatic stream, [7] especially in metastatic angiosarcomas, wherein 42.6% of patients developed bone metastases. [8] Although fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) is regarded as a reliable and indispensable imaging method for evaluating and staging bone metastases of angiosarcoma, [9][10][11][12][13][14] here we report 2 cases of angiosarcoma with bone metastases that presented with "false negative" findings on 18 F-FDG PET/ CT. To the best of our knowledge, there has been only 1 report of false-negative findings of bone metastases of angiosarcoma on 18 F-FDG PET/CT.

Case 1
A 39-year-old woman, who had no history of diabetes mellitus, presented with right coxalgia that had persisted for approximately 5 months. The patient first noticed a mass in her right breast 2 years prior, which had subsequently enlarged. One year later, the patient was diagnosed with angiosarcoma of the breast and underwent a mastectomy. Another year later, right coxalgia gradually appeared. Since there were no abnormal findings on radiographs, magnetic resonance imaging (MRI) was performed. Although MRI indicated bone lesions in the right acetabulum and left ischium ( Fig. 1A and B), bone scintigraphy and 18 F-FDG PET/CT revealed no abnormal uptake or osteolytic destruction ( Fig. 1C-E). Therefore, the bone lesions were considered benign and were followed-up conservatively. Nevertheless, the patient's right coxalgia worsened, and the patient was finally referred to our hospital. The multiple bone lesions detected on MRI were inconsistent with benign bone tumors and suggested the presence of bone metastases. There were no metastases present in other organs. An open biopsy of the left ischiatic lesion was conducted the following month. The pathological diagnosis was angiosarcoma, consistent with metastasis from the breast. The tumor was composed of numerous irregular anastomosing vascular channels lined by atypical endothelial cells with enlarged nuclei (Fig. 2). The patient was administered weekly paclitaxel (wPTX) treatment in the same month.

Case 2
A 37-year-old woman presented with gradually enlarging mass in her left breast for the past 4 years. The patient had never been  diagnosed with diabetes mellitus. One and a half years later, the patient was diagnosed with primary angiosarcoma of the breast, without any distant metastases, and underwent a mastectomy.
Two and a half years after the mastectomy, during postoperative follow-up, a local recurrence in the left intercostal muscle was detected on 18 F-FDG PET/CT ( Fig. 3A and B). MRI indicated local recurrence (Fig.3C) in the left intercostal muscle, and additionally indicated a bone metastasis in the sternum (Fig. 3E), which showed no uptake on 18 F-FDG PET/CT (Fig. 3D). Furthermore, enhanced CT detected a liver tumor (Fig. 4). Liver biopsy revealed that the liver tumor was consistent with angiosarcoma metastasis. Finally, the patient was diagnosed with local recurrence of the left intercostal muscle and distant metastases to the sternum and the liver, resulting from primary angiosarcoma of the left breast. wPTX was initiated as a salvage chemotherapy. After the second course of wPTX, MRI showed multiple bone metastases (the sternum and the fifth thoracic vertebra) (Fig. 5A). However, 18 F-FDG PET/CT indicated no obvious uptake in the multiple bone metastatic lesions (Fig. 5B).

Discussion
18 F-FDG PET/CT is considered useful not only for localization but also for the differentiation of vascular tumors, such as angiosarcoma, hemangioma, and epithelioid hemangioendothelioma, according to differences in FDG uptake patterns. It has been reported that standardized uptake value (SUV) max can be used to evaluate the status of vascular tumors. [15] Several reports have demonstrated that 18 F-FDG PET/CT could be used for pathological and prognostic evaluation of angiosarcoma, as well as its localization. Kato et al [7] reported that the SUVmax at initial presentation correlated with the grading and overall survival of angiosarcoma. Umemura et al [16] reported that  cutaneous angiosarcomas with a higher SUVmax at the initial diagnosis had a significantly poorer prognosis than those with a lower SUVmax. Recently, Chen et al [17] demonstrated that 18 F-FDG PET/CT was highly sensitive and specific for detecting bone metastases of angiosarcoma, especially occult bone metastases, and that bone metastases detected by 18 F-FDG PET/CT were poor prognostic factors for angiosarcoma. Considering its impact on the treatment plan as well as the patients' quality of life or activities of daily living, such as pain and impending fracture, accurate early diagnosis of bone metastasis of angiosarcoma is important. Generally, bone metastases on 18 F-FDG PET/CT are detected by abnormal FDG uptake accompanied by osteolytic destruction, which is often consistent with MRI findings. [17] In the 2 cases presented here, however, MRI showed multiple bone lesions, while 18 F-FDG PET/CT detected neither uptake nor osteolytic destruction. To the best of our knowledge, there has been only 1 report of false-negative findings of bone metastases of angiosarcoma on 18 F-FDG PET/CT. Among the 19 cases of angiosarcoma analyzed by Chen et al, bone metastases were found in 10 cases; however, 2 of them showed no uptake on 18 F-FDG PET/CT, nor did they show osteolytic destruction. Chen et al [17] did not mention the primary site of angiosarcoma in the 2 cases presenting false-negative findings. In both cases presented herein, the primary sites were angiosarcomas of the breast, which suggests that the primary site of angiosarcoma is related to false-negative results of bone metastases on 18 F-FDG PET/CT.
Regarding the false-negative findings of bone metastases of sarcomas on 18 F-FDG PET/CT, Aryal et al [18] compared the accuracy of 18 F-FDG PET/CT, bone scintigraphy, and whole-body MRI for staging diagnosis in 54 patients with osteosarcoma and Ewing sarcoma and found no significant difference among the 3 methods. On the other hand, Bosma et al [19] examined the ability of MRI and 18 F-FDG PET/CT to detect bone metastases in 112 bone specimens obtained from 20 patients with Ewing sarcoma. They found that 18 F-FDG PET/CT tended to show false-negative findings of bone metastases compared to MRI when bone marrow hematopoiesis was active. This may be because the boundary between bone metastases and normal bone is unclear. The authors also noted that the variables of "active bone marrow hematopoiesis," "under chemotherapy," and "small tumor size" significantly reduced the detection rate of bone metastases on 18 F-FDG PET/CT compared to MRI.
In both cases detailed in this case series, relatively small metastatic bone lesions with preserved bone trabecular structure may be collated with false-negative results on 18 F-FDG PET/ CT. Especially in Case 2, the 18 F-FDG PET/CTs were performed during chemotherapy, which is consistent with one of the conditions for false-negative findings, as reported by Bosma et al. [19] Although 18 F-FDG PET/CT is frequently used in the evaluation of distant metastases and clinical staging of angiosarcomas, the possibility of false-negative findings should be considered, especially in the evaluation of bone metastases. Follow-up imaging studies, including MRI or open biopsy, should be performed.